Localized delivery of therapeutics via biodegradable nanoparticles often provides advantages over systemic drug administration, including reduced systemic side effects and controlled drug levels at target sites. However, controlled tog delivery at mucosal solaces has been limited by the presence of the protective mucus layer.
Mucus is a viscoelastic gel that coats all exposed epithelial surfaces not covered by skin, such as respiratory, gastrointestinal nasopharyngeal, and female reproductive tracts, and the surface of eye. Mucus efficiently traps conventional particulate drug delivery systems via steric and/or adhesive interactions. As a result of mucus turnover, most therapeutics delivered locally to mucosal surfaces suffer from poor retention and distribution, which limits their efficacy.
Drug and gene carrying nanoparticles delivered to mucus-covered cells in the eyes, nose, lungs, gastrointestinal tract, and female reproductive tract roust achieve uniform distribution in order to maximally treat or protect these surfaces. However, the highly viscoelastic (i.e., viscous and solid-like in nature) and adhesive mucus layer can slow or completely immobilize particles, and thereby prevent them from spreading over the mucosal surface. In addition, some mucosal surfaces, such as those of the mouth, stomach, intestines, colon, and vagina, exhibit highly folded epithelial surfaces that are inaccessible to conventional muco-adhesive particles and also to many small molecule drugs and therapeutics. Without maximal distribution with penetration into these deep recesses, much of the epithelium is left susceptible and/or untreated. Additionally, penetration into the folds, presumably containing a much more slowly cleared mucus layer, allows for increased residence time at the epithelial surface.
For drug or gene delivery applications, therapeutic particles must be able to 1) achieve uniform distribution over the mucosal surface of interest, as well as 2) cross the mucus barrier efficiency to avoid rapid mucus clearance and ensure effective delivery of their therapeutic payload to underlying cells (das Neves J & Bahia. M F Int J Pharm 318, 1-14 (2006); Lai et al. Adv Drug Deliver Rev 61, 158-171 (2009); Ensign et al. Sci Transl Med 4, 138ra179 (2012); Byles et al. J Pharm Pharmacol 47, 561-565 (1995)).
Biodegradable nanoparticles that penetrate deep into the mucus barrier can provide improved drug distribution, retention and efficacy at mucosal surfaces. Dense surface coats of low molecular weight polyethylene glycol (PEG) allow nanoparticles to rapidly penetrate through highly viscoelastic human and animal mucus secretions. The hydrophilic and bioinert PEG coating effectively minimizes adhesive interactions between nanoparticles and mucus constituents. Biodegradable mucus-penetrating particles (MPPs) have been prepared by physical adsorption of certain PLURONICs, such as F127, onto pre-fabricated mucoadhesive nanoparticles.
The surface of the vagina is highly folded to accommodate expansion during intercourse and childbirth; these folds, or “rugae,” are normally collapsed by intra-abdominal pressure, hindering drug delivery to the folded surfaces. For truly effective prevention and treatment, sustained drag concentrations must be delivered to, maintained over the entire susceptible surface. Failure to achieve adequate distribution over the vaginal epithelium is a documented failure mode of vaginal microbicides.
Another significant barrier to effective drug delivery to the vagina is the viscoelastic layer of mucus secreted by the endocervix that coats the vaginal epithelium. Mucus efficiently traps foreign particles and particulates by both steric and adhesive mechanisms, facilitating rapid clearance. Although the use of mucoadhesive dosage forms has been proposed for increasing residence time in the vagina, mucus clearance occurs rapidly (on the order of minutes to hours), limiting the residence time of mucoadhesive systems.
Mucosal epithelia use osmotic gradients to cause fluid absorption and secretion. Vaginal products have traditionally been made with hypertonic formulations, including yeast infection treatments, most sexual lubricants such KY® warming gel, and gels designed for preventing sexually transmitted infections such as HIV. Hypertonic formulations cause rapid, osmotically-driven secretion of fluid into the vagina, and this causes an immediate increase in fluid leakage from the vagina at a rate proportional to the hypertonicity of the formulation. Moreover, recent investigations of candidate vaginal and rectal microbicides both in animal models and in humans have revealed feat hypertonic formulations cause toxic effects that can increase susceptibility to infections. The first successful microbicide trial for HIV prevention found that the antiretroviral drug, tenofovir, delivered in a vaginal gel, provided partial protection. Unfortunately, the gel was highly hypertonic, leading investigators in the most recent clinical trial of tenofovir to reduce the concentration of glycerol to reduce toxicity. However, the concentration was not reduced, and the formulation is still significantly hypertonic. There appears to be no evidence to justify hypertonic formulations for vaginal drug delivery, since in addition to the documented toxic effects, hypertonic formulations cause rapid osmotically-driven secretion of vaginal fluid, fluid flow that opposes the delivery of drugs to the epithelium. This lack of justification has been ignored by both investigators and manufacturers of vaginal products, the only evident exception being sexual lubricants intended to support fertilization. These products are formulated to be isotonic (the osmolality is equivalent to that of plasma) to help maintain viability of sperm.
Therefore, it is an object of the invention to provide formulations for rapid and uniform particulate delivery of a wide range of drugs to mucosal covered epithelial surfaces with minimal toxicity to the epithelium.